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Increased post-mitotic senescence in aged human neurons is a pathological feature of Alzheimer's disease
Joseph R Herdy 1, Larissa Traxler 2, Ravi K Agarwal 3, Lukas Karbacher 3, Johannes C M Schlachetzki 4, Lena Boehnke 2, Dina Zangwill 5, Doug Galasko 6, Christopher K Glass 4, Jerome Mertens 7, Fred H Gage 8
...We found that Alzheimer's disease (AD) brains have significantly higher proportions of neurons that express senescence markers, and their distribution indicates bystander effects. AD patient-derived directly induced neurons (iNs) exhibit strong transcriptomic, epigenetic, and molecular biomarker signatures, indicating a specific human neuronal senescence-like state. AD iN single-cell transcriptomics revealed that senescent-like neurons face oncogenic challenges and metabolic dysfunction as well as display a pro-inflammatory signature. Integrative profiling of the inflammatory secretome of AD iNs and patient cerebral spinal fluid revealed a neuronal senescence-associated secretory phenotype that could trigger astrogliosis in human astrocytes. Finally, we show that targeting senescence-like neurons with senotherapeutics could be a strategy for preventing or treating AD.